Role of C5a and C5aR in doxorubicin‑induced cardiomyocyte senescence

Abstract

Doxorubicin (DOX) is an efficacious antineoplastic drug; however, its use is limited due to its cardiotoxicity. Cardiomyocyte senescence is considered to be a key factor in the development of DOX-related cardiomyopathy. Complement component 5a (C5a) and the C5a receptor (C5aR) have been reported to play a key role in the process of cellular senescence. However, to the best of our knowledge, the exact role of C5a and C5aR in cellular senescence in the heart remains largely unknown. Reverse transcription-quantitative (RT-q)PCR and western blot assays were used to analyze the expression levels of C5a and C5aR in H9c2 embryonic rat cardiomyocytes and AC16 human cardiomyocyte-like cells. The cells were treated with DOX and a C5aR antagonist (C5aRA). The expression of TNF-α and IFN-γ was determined using ELISA and western blotting. The levels of reactive oxygen species (ROS) were also measured using ELISA. Cellular senescence was determined using senescence-associated β-galactosidase (SA-β-gal) staining and by analyzing the protein expression levels of p53, p16, p21 and insulin-like growth factor-binding protein 3 (IGFBP3). The expression levels of C5a and C5aR were found to be upregulated during the DOX-induced senescence of H9c2 and AC16 cardiomyocytes. Treatment with C5aRA downregulated TNF-α and IFN-γ expression, in addition to ROS levels. Furthermore, C5aRA prevented DOX-induced cellular senescence and decreased the levels of positive SA-β-gal staining in H9c2 and AC16 cardiomyocytes, in addition to downregulating the expression levels of p53, p16, p21 and IGFBP3. C5aRA also increased the telomere length and telomerase activity in H9c2 and AC16 cardiomyocytes following DOX stimulation. In conclusion, the findings of the present study indicated that C5a and C5aR may play a key role in cardiomyocyte senescence, and treatment with C5aRA may be an effective method for preventing DOX-induced cardiomyocyte aging.

Valproic acid attenuates cellular senescence in diabetic kidney disease through the inhibition of complement C5a receptors

“…However, the role of the complement system in inflammaging and senescence in DKD is less well known. Previous studies have reported a role for C5a in cellular senescence 15 , 39 . Castellano and colleagues first reported that C5a induced cellular senescence through epigenetic modifications in renal tubular epithelial cells (RTEC) 15 .…”